Coronary heart disease is one of the major causes of death in the industrialized world. The major coronary heart disease (CHD) risk factors are hyperlipidemia, type 2 diabetes / impaired glucose tolerance (IGT), obesity and essential hypertension, that is, a form of hypertension occurring without discoverable organic cause. The coronary heart disease risk factor syndrome (CHDRF syndrome) may be defined as a group of diseases, that is, hyperlidemia, Type 2 diabetes / impaired glucose tolerance (IGT), obesity and essential hypertension which individually, and together are among the major risk factors in coronary heart disease. The disease states which make up the syndrome of the coronary heart disease risk factors (CHDRF syndrome) are all interrelated. However, the exact interrelationship between the disease states making up the syndrome is not frilly understood. There are a wide variety of chemical and physical abnormalities associated with the CHDRF syndrome. These abnormalities include elevation in fasting blood glucose, elevation of HgbAlc, elevation of C-peptide, elevation of fasting total cholesterol, elevation of fasting LDL-cholesterol, decrease in fasting HDL-cholesterol, a high LDL/HDL ratio, elevation of fasting triglycerides, elevation of fasting free fatty acid concentration, elevation in body weight, elevation of systolic blood pressure, and elevation of diastolic blood pressure.
Although the entire CHDRFS is interrelated, individual patients may not present all the symptoms associated with the syndrome. Accordingly, in some patients the lipid metabolism problems may predominate, while in others, the glucose metabolism problems play a more major role. The factors, which lead one aspect of the syndrome to predominate over another, are not well understood. However, it is clear that each portion of the syndrome, or combination of portions of the syndrome, represents a risk factor in coronary heart disease.
Hyperlipidemia, also called dislipidemia, is characterized by elevated levels of total and low density lipoprotein cholesterol (LDL cholesterol), elevated levels of triglycerides and low levels of high density lipoprotein cholesterol (HDL cholesterol), as well as elevated levels of free fatty acids. State-of-the-art therapeutic regimens have failed to treat and correct the entire complex of hyperlipidemia with a single pharmaceutical agent. Drugs such as clofibrate/gemfibrozil lower triglycerides, by some unknown mechanism, but have no effect of the free fatty acid level, and no effect upon the total cholesterol level. However, the drugs may shift the proportion of cholesterol found in the form of low and high density lipoprotein cholesterol. In patients suffering from an elevated level of low density lipoprotein cholesterol, the drugs may actually further increase the level of low density lipoprotein cholesterol. Drugs like lovastatin, on the other hand, lower the level of both total and low density lipoprotein cholesterol, while slightly increasing the level of high density lipoprotein cholesterol. However, these drugs have no effect on free fatty acids and little or no effect on triglyceride levels.
Lipid metabolism is rather complex. While it is clear that hyperlipidemia is associated with the development of coronary heart disease, there is no clear understanding of the pathogenic causes and pathways leading up to the manifestation of the various lipid disorders, nor is there any agreement as to the relative roles of lipid ingestion versus endogenous lipogenesis in the etiology of lipid abnormnalities. Insulin resistance has, traditionally, been considered a state in which a normal amount of insulin produces a subnormal biological response, as is the case in non-insulin-dependent diabetics and/or in pre-diabetic subjects affected by glucose intolerance or impaired glucose tolerance. These subjects require (and endogenously produce) higher than normal levels of insulin to compensate for their insulin resistance to normalize their blood glucose levels. As a consequence, the traditional definition of insulin resistance was expressed in the insulin/glucose ratio (I/G). It has only been recently that other biological functions of insulin have become the focus of more intense scientific interest, e.g. the role of insulin in endogenous lipogenesis. Although an interaction between obesity and insulin resistance has been established, the cause and effect relationship between these syndromes is still hotly debated in the scientific community: which comes first, insulin resistance or obesity or hyperlipidemia. Whatever the exact cause(s) of hyperlipidemia may be, current therapeutic modalities of lowering one or the other lipid fraction are not capable of correcting the entire hyperlipidemic complex at or close to its original cause.
Type 2 diabetes, also known as maturity-onset diabetes, as opposed to type 1 diabetes, or juvenile diabetes, is characterized by inadequate endogenous insulin concentrations, although, in absolute terms, the insulin concentrations in type 2 diabetics may, in fact, be higher than in the normal population. A possible explanation for this apparent discrepancy may lie in the fact that type 2 diabetics, as well as subjects with impaired glucose tolerance (IGT), typically require more insulin to control their blood sugar level. The requirement for more insulin may be caused, in part, by a resistance to the action of insulin on the control of glucose. It is important to note that resistance to the action of insulin on the control of glucose may not carry over to the action of insulin on lipogenesis. Even though the patient is resistant to the action of insulin in controlling glucose, the response of lipid metabolism to insulin may remain. Thus, when the level of insulin rises due to the patient's insulin resistance, the elevation in insulin concentration may cause an increase in lipogenesis which, in turn, may lead to hyperlipidemia Current pharmaceutical modalities to treat the symptoms of type 2 diabetes have generally no beneficial effect on hyperlipidemia; some of the widely used medicines to treat type 2 diabetes, e.g. the sulfonylureas, tend to increase hyperlipidemia. Impaired glucose tolerance can be considered a precursor of type 2 diabetes. IGT is a phase at which the abnormal elevation of insulin concentration is still able to maintain a normal fasting blood sugar level. Over time, the insulin releasing beta-cells appear to lose their ability to produce enough insulin, and the subject slowly `decompensates` to the state of `overt` diabetes.
Obesity is now being recognized as a disease of major proportions and severe economic consequences, and not merely a physical or cosmetic inconvenience. Obesity is second only to cigarette smoking as a preventable cause of premature death, and its complications add $ 100 billion to the U.S. health care cost. Obesity can not be treated effectively by willpower alone, and pharmaceutical drugs, currently available are either in-effective long-term, or carry the risk of potentially fatal side-effects, like pulmonary hypertension or heart defects in connection with dexfenfluramin or fenfluramine. Six out of ten, or approximately 130 million people, in the United States are overweight, close to 90 million are obese and 22 million are morbidly obese.
The definition of obesity and normal weight is somewhat arbitrary. The disease of being overweight or obese is characterized by excess body fat, that is, the body contains a level of fat beyond that considered normal. Often, body weight in relationship to height and build is used as a surrogate measure. A weight of 20% over that in the standard height weight tables is considered obese. Normal weight has several definitions. The body mass index (BMI) is commonly used in defining normal weight. The BMI is calculated by dividing a person's weight in kilograms by the square of height in meters (kg/m.sup.2) or (lbs..times.705/inches.sup.2). A BMI of 25 is considered normal, a BMI of 25-27 is considered overweight, a BMI 27-40 is considered obese, and a BMI&gt;40 is considered morbid. A therapeutic intervention is considered effective if it produces a weight reduction of &gt;10% or a reduction by &gt;5% if `co-morbid` factors are also improved, e.g. hyperlipidemia or diabetes.
Hyperlidemia, also known as disilpidemia, is a group of conditions characterized by the elevation of one or more of the following lipid materials: free fatty acids, triglycerides, total cholesterol, and low density lipoprotein cholesterol. Hyperlipidemia may also be associated with decreased high density lipoprotein cholesterol.
During the investigations into, and development of non-addictive morphine based analgesics, typically requiring a combination of agonistic and antagonistic actions at various opiate receptor sites, i.e. .mu., .delta. and .kappa. receptors, a variety of so-called `pure` antagonists have evolved as by-products, and some of these narcotic antagonists, or anti-opioids, have been shown to have potential in the treatment of a variety of disease conditions.
U.S. Pat. No. 4,272,540 discloses various 14-methoxy substituted 3-hydroxy or 3-methoxy-6-one morphinans, which are variously useful as analgesics, narcotic antagonists, and mixed analgesics and narcotic antagonists.
U.S. Pat. No. 4,451,470 discloses 14-fluoromorphinans which are useful as analgesic, narcotic antagonists and/or anorexigenic agents.
U.S. Pat. No. 4,478,840 discloses 17-cycloalkylmethyl-4-5.alpha.-epoxymorphinan-3,14-diol compounds useful for suppression of appetite in mammals.
U.S. Pat. No. 4,511,570 discloses a method of treating senile dementia which comprises periodic oral delivery of a pharmaceutically effective amount of 6-methylen-6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphone.
U.S. Pat. No. 4,619,936 discloses pharmaceutical compositions containing (5.alpha.,6.alpha.)7,8-didehydro-4,5-epoxy-17-(2-propanyl)-morphinano-3,6- diol for the purpose of appetite reduction.
U.S. Pat. No. 4,857,533 discloses a method of treating a human or animal patient suffering from an autoimmune disease, which comprises the daily administration of the narcotic antagonists nalmefene or naltrexone.
U.S. Pat. No. 4,863,928 discloses a method of treating a human or animal patient suffering from an arthritic disease which comprises the daily administration of the narcotic antagonists nalmefene or naltrexone.
U.S. Pat. No. 4,877,791 discloses a method of treating a human or animal patient suffering from intestinal cystitis which comprises the daily administration of the narcotic antagonists nalmefene or naltrexone.
U.S. Pat. No. 4,880,813 discloses a method of treating patients suffering from allergic rhinitis, which comprises the topical administration to the nasal passages of the narcotic antagonist nalmefene or a salt thereof
U.S. Pat. No. 4,882,335 discloses a method useful as an adjunct in the treatment of alcoholism. The method involves having the patient drink alcoholic beverages, while an opiate antagonist blocks the positive reinforcement effects of ethanol in the brain.
U.S. Pat. No. 4,994,466 discloses a method of treating a human or animal patient suffering from multiple sclerosis, which comprises the daily administration to such patient of a pure narcotic antagonist, e.g., nalmefene or naltrexone.
U.S. Pat. No. 5,086,058 discloses a method for treating alcoholism. The method involves having the patient drink alcoholic beverages while nalmefene, an opiate antagonist, blocks the positive reinforcement effects of ethanol in the brain.
U.S. Pat. NO. 5,356,900 discloses a method of treating a human patient suffering from chronic herpes virus infections which comprises administration to such patient of an essentially pure narcotic antagonist exhibiting substantially higher blocking action against .mu. opiate receptor sites than against 67 receptor sites.
U.S. Pat. No. 5,468,755 discloses a process for the long term modification and regulation of lipid and carbohydrate metabolism--generally to reduce obesity, insulin resistance, and hyperinsulinemia or hyperglycemia, or both (these are the hallmarks of noninsulin dependent, or type 2 diabetes)--by administration to a patient of a dopamine agonist, e.g. bromocriptine. Administration of the bromocriptine is made over a limited period at a time of day dependent on the normal circadian rhythm of insulin resistant and insulin sensitive humans. The process may be applied to other vertebrate animals.
U.S. Pat. No. 5,626,860 discloses a method for regulating or ameliorating lipid and glucose metabolism, and reducing body fat stores, insulin resistance, hyerinsulinemia, hyperglycemia, hyperlipidemia, elevated blood lipoproteins (such as triglycerides and cholesterol including chylomicrons, VLDL an LDL) and/or increasing in the subject the plasma HDL. The methods comprises administration or timed administration of inhibitors of dopamine beta hydroxylase (DBH), such as fusaric acid and disulfiram. The preferred daily dose of fusaric acid is 5 to 150 mg/kg of body weight. The preferred daily dose of disulfiram is 100 to 500 mg/kg of body weight or 800 to 40,000 mg/day for a subject weighing 80 Kg.
The Merck Index 10.sup.th Ed., 1983 pp. 491-2 discloses that administration of alcohol after disulfiram therapy causes intense vasodialation of face and neck, tachycardia, and tachypnea followed by nausea, vomiting, pallor and hypotension. Ocassionally convulsions, cardiac arrhythmias, myocardial infarctions may occur. High doses of alcohol, in combination with disulfiram, my cause dizziness, headache, dyspnea unconsciousness, or death.
The Merck Index 10.sup.th Ed., 1983 p. 883 discloses that metyrosine is an inhibitor of the first and rate-limiting step in catecholamine biosynthesis, hydroxylation of tyrosine to dopa.
The Pharmacological Basis of Therapeutics, Seventh edition (Chapter 18 P.383), 1985 discloses that that the use of disulfuram therapy should be attempted only under careful medical and nursing supervision.
It has been shown that bromocriptine improves glucose tolerance, and decreases insulin values toward normal in patients with prolactin-producing tumors of the pituitary gland. (R. Landgraf et al; Diabetologia 13, 1977, pp. 99-104).
Naltrexone, an antiopioid with unequal opioid receptor binding, by an order of magnitude, has been used in an attempt to reduce body weight, but with inconsistent results. (Atkinson et al, Clin. Pharnacol. Ther. 10/85:pp 419-422). This report has also raised questions about a potential hepatic toxicity of naltrexone in humans.
Elevated insulin concentrations have been reduced, for a period of a few days, in a select patient population of four women with polycystic ovary syndrome with Acanthosis Nigrians, by administration of Nalmefene (J. R. Givens et al; J. Clin. Endocr. & Metab. 64/2, 1987, pp.377-382). Nalmefene, (6-desoxy-6-methylene-naltrexone), is an anti-opioid with a structure and relative receptor binding characteristics similar to naltrexone, but of increased potency and without hepatic toxicity. This report covers concentrations of insulin and glucose, the insulin glucose ratio (I/G) as a measure of insulin resistance, as well as growth hormone (GH), luteinizing hormone LH), follicle stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS), cortisol, testosterone and prolactin (PRL) levels during the study. This report does, however, not report any values on blood lipids, i.e. free fatty acids (FFA), triglycerides (TG), and any of the cholesterol fractions.
It has been shown that intracisternal administration of synthetic human .beta.-endorphin in chronically cannulated, conscious, freely moving, adult male rats increased plasma concentrations of epinephrine, norepinephine, and dopamine in a dose related manner (G. R. Van Loon, N. M. Appel and D. Ho; Endocrinology; Vol. 109, P. 46, 1981). This is consistent with the hypothesis that endorphins act at unknown sites to increase peripheral catecholamine release. However, the effect of endorphins upon catecholamine binding is not disclosed.
It has been shown that a .kappa.-selective antagonist, nor-binaltorphimine improves the outcome after experimental brain trauma (R. Vink, P. S. Portoghese, and A. I. Faden, Am. J. Physiol. 261, 1991). The .kappa.-opioid receptors apparently mediate pathophsysiological changes after traumatic brain injury. The structure of nor-binaltorphimine is shown by the following formula: ##STR1##
Opiate antagonists, or anti-opioids are molecular structures similar to opiates but without any agonist activity. They have the ability to reduce or prevent the receptor binding of opiate agonists, thus neutralizing their biologic effect. Anti-opioids, or narcotic antagonists, are characterized by their ability to displace narcotic agonists from the respective receptors, and since narcotics, in general, possess several agonist actions, e.g. .mu., .delta., and .kappa., anti-opioids, typically, possess antagonist capabilities for those receptors as well. In general, the antagonist activity, or effectiveness of anti-opioids at the various receptor sites is not equal and may vary significantly, oftentimes by more than an order of magnitude. In such case, e.g. for naltrexone, the .mu. receptor binding effectiveness is 12 times higher than its effectiveness to bind to a .kappa. receptor, which will result in a 12-fold increase of agonist displacement at the .mu. receptor over the .kappa. receptor. Since the .mu. receptor is known to control (amongst others) euphoria, a suppression of this action 12-fold over any action controlled by .kappa., e.g. various metabolic functions, can, actually result in disphoria, if the antiopioid dosage has to be increased to achieve the desired effect at the .kappa. site.
IC.sub.50 is defined as the concentration of a compound at which 50% of the standard molecule is displaced from the target receptor. For each receptor there is a prototype ligand. To measure the IC.sub.50 for given anti-opioid, one measures the concentration of the anti-opioid which will drive 50% of the prototype ligand from the target receptor. For the .mu. receptor the prototype ligand is DHM (dihydromorphine). For the .delta. receptor, the prototype ligand is DADLE (D-Ala+D-Leu-Enkephalin), and for the .kappa. receptor, the prototype ligand is EKC (ethylketocyclazocine).